Alkyl Halides (Haloalkanes)
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1
Structure of Alkyl Halides
Cl
Cl
C
CH3 CH
Cl
CH
Tetrachloromethane
or carbon tetrachloride
CH3 CH
CH3
Cl
Cl
CH3
CH2 CH2
Cl
Br
2-Chloro-3-methylbutane
3-Bromo-1-chlorobutane
CH2CH3
Br
F
1-Bromobutane
1-Ethyl-2-fluorocyclohexane
F
Cl
Cl
C
Cl
Cl
F
Trichlorofluoromethane
(Freon-11)
Cl
C
Cl
F
F
2-Chloropropane or
Isopropyl chloride
F
F
C
C
F
H
H
Dichlorodifluoromethane
1,1,1, 2-Tetrafluoroethane
(Freon-12)
Chlorofluorocarbons (CFCs) :Refrigerant Gases, Ozone Depletion
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2
Halothane (Fluothane)
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3
Physical Properties of
Alkyl Halides
• Most alkyl halides are liquids at room
temperature.
• Liquid alkyl halides are insoluble in water
and more dense than water.
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4
Reactions of Alkyl halides
Alkyl Halides: R-X
The carbon center is sp3 hybridized in alkyl halides and the C-X bond is
polarized as shown because of the greater electronegativity of the
halogen.
δ+ δ−
C X
Electronegativity is defined as the ability of atoms to attract shared
electrons in a covalent bond ------------ leads to nucleophilic
substitution in alkyl halides
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Nucleophilic Substitution Reactions
A characteristic reaction of alkyl halides is nucleophilic substitution
where a nucleophile with an unshared pair of electrons replaces the
halogen.
R-Nu
alkyl halide
substrate
product
:X
+
-
:
R-X
: :
:
nucleophile
+
: :
-
Nu:
halide ion
Substitution occurs by bond heterolysis:
Nu: R +
:
::
bond heterolysis
:X : :
: :
Nu:- + R X
electron pair
from nucleophile
Examples of Nucleophilic Substitution
:
Cl:
CH3CH2-I + Cl
-
: :
:
+ CH3CH2- Cl:
-
: : : :
: :
I
+
CH3-OH
: :
: :
-
+ CH3-Cl:
: :
HO:
: : : :
: :
-
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Nucleophiles
A nucleophile has an unshared pair of electrons available
for bonding to a positive center.
Nucleophiles may be negatively charged:
NH2
: : ::
: :
:
:
: :
or neutral:
:
- -
: :
-
: :
: :
-
HO , CH3O , I ,
H2O , H3N, CH3OH
The polarity of the
δ+
C
X δ−
carbon-halogen bond
determines the
reactivity pattern: Nucleophiles attack
Halide ion
is the leaving
group.
electropositive center.
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7
Examples
H
(1)
HO
-
+
nucleophile
C
Cl
H
H3C
substrate
H
(2) H
O
H+
nucleophile
C
Cl
H
H3C
substrate
H
H
H3C
C
OH
product
+
Cl
leaving group
H
C O H
H
H3C
H
ethyloxonium ion
+
Cl
leaving group
H2O
H
H
H3C
C
product
OH + H3O
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Leaving Groups
The halogen is only one of many leaving groups, "L". A more general
description of nucleophilic substitution is :
-
Nu:
+
R-Nu
R-L
+
L:leaving group
A good leaving group produces a stable anion or neutral molecule.
Generally, the anions (conjugate bases) of strong acids are good
leaving groups.
H-A
strong acid
+ H2O
+
H3O
+
A:-
anion
very stable
A good
leaving group
in R-A .
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Neutral Molecules as Leaving Groups
Poor leaving groups can
be turned into good
CH3-OH
leaving groups by
protonation.
Hydroxide ion is a
poor leaving group
because it is the anion
of a weak acid, H2O.
In the presence of a strong acid,
: :
CH3OH
H2SO4
+
+
CH3OH +
H
HSO4
a nucleophilic substitution reaction occurs:
CH3OH
nucleophile
+
+
CH3OH
H
+
CH3OCH3
H
+
H2O
leaving group
good leaving group
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11
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A Mechanism for the SN2 Reaction
In 1937 Edward Hughes and Sir Christopher Ingold proposed a
mechanism to explain the second order kinetics and other important
features of this nucleophilic substitution reaction that were known at
that time.
The Hughes-Ingold Mechanism for the SN2 Reaction
In their mechanism, the nucleophile attacks the carbon center on the side
opposite the leaving group. As overlap develops between the orbital with
the electron pair of the nucleophile and the antibonding orbital of the
substrate, the bond between the carbon and the leaving group weakens.
OH-
H
H
C
H
Cl
δ−
HO
H
C
HH
TS
δ−
Cl
H
HO
C
+ Cl
H
-
H
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SN2 reaction
All SN2 reactions proceed with
backside attack of the
nucleophile, resulting in
inversion of configuration at
the stereogenic center.
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Examples of inversion of configuration in the SN2 reaction
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Reaction of t-Butyl Chloride with Hydroxide: SN1 Reaction
The reaction of t-butyl chloride with sodium hydroxide in a mixture of
water and acetone (to help dissolve the RCl) shows the following rate
expression:
CH3
CH3-C-Cl
CH3
+ HO-
H2O
acetone
CH3
CH3-C-OH
CH3
+ Cl-
The reaction rate depends on the concentration of t-butyl chloride, but
shows no dependence on the concentration of hydroxide ion.
A reaction rate that depends on
the concentration of only one
The symbol is SN1.
reactant (to the first power) is
called first-order or unimolecular.
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SN1 reaction
The key features
1. The mechanism has two steps.
2. Carbocations are formed as
reactive intermediates.
3. Reactions proceed with
racemization at a single
stereogenic center.
Relative stabilities of carbocations
R
R C+
R
3o
most stable
>
R
R C+
H
2o
>
H
R C+
H
1o
>
H
H C+
H
methyl
least stable
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Use of the SN2 Reaction in Organic Synthesis
The conversion of one compound into another through a chemical
reaction is called synthesis. The SN2 reaction is often used to convert
alkyl halides into other functional groups.
Nucleophiles
HO-
alcohols
R'O-
R-OR'
ethers
HS-
R-SH
thiols
-:CN
R-CN
nitriles
R'C
C:-
O
R'-C-O-
CR' alkynes
O
R-O-C-R' esters
R'3N:
R-NR'3
ammonium
ion
N3-
R-N3
azides
RC
=
=
R-X
for R= CH3, 1o, 2o
X = Cl,Br, I
R-OH
+
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18
Stereochemistry of SN2 Synthetic Reactions
As in all SN2 reactions, these syntheses proceed
with inversion at a stereocenter.
N
C
+
H3C
CH3
C
H
H3CH2C
Br
(R)-2-bromobutane
N
C
C H
CH2CH3
(S)-2-methylbutanenitrile
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Elimination Reactions of Alkyl Halides
In an elimination reaction, the atoms or groups X and Y are lost from
adjacent carbons forming a multiple bond.
C C
X Y
C C
(-XY)
The Dehydrohalogenation Reaction
A standard synthesis of
alkenes is the
dehydrohalogenation
reaction of alkyl halides.
C C
X H
(-HX)
alkyl halide
C C
alkene
Example: The Dehydrobromination of tert-Butyl Bromide
CH3
CH3C-Br + NaOCH2CH3
CH3
tert-butyl bromide
CH2=C
CH3
CH3
isobutene
+ HOCH2CH3
+ Na+ Br20
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A Beta- or 1,2-Elimination Reaction
This reaction is described as a beta-elimination or 1,2-elimination
indicating the positions of the lost atoms or groups.
H
H
CH3
C
C
β position H
(-HBr)
Br
β
α CH3
or
CH2 C
CH3 α position
2
CH2
CH3
1 CH3
C
CH3
The α or 1 position is the carbon with the halogen leaving group.
The Role of Base in Dehydrohalogenation Reactions
A number of different bases may be used in the dehydrohalogenation
reaction. Typical bases are potassium hydroxide in ethanol (to solubilize
the alkyl halide) or sodium ethoxide in ethanol. Potassium tert-butoxide
is another oxygen base that is often used in dehydrohalogenation
reactions.
Some Oxygen Bases
KOH
NaOEt
KOBu-t
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Mechanism of Dehydrohalogenation: The E2 Reaction
The reaction of isopropyl bromide with sodium ethoxide in ethanol to
give propene:
CH3CH=CH2 +
Br
propene
CH3CHCH3 + NaOCH2CH3
ethanol
isopropyl bromide sodium ethoxide
HOCH2CH3 + Na+Br-
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A Mechanism for the E2 Reaction
The mechanism proposed for the E2 reaction is based on the observed
second order rate expression, as well as the stereochemical outcome
observed in alkyl halides with multiple stereocenters. The E2 like the
SN2 is a single step mechanism .
CH3CH2O-
H CH3
H
H
C
H
δ−
CH3CH2O
C
Br
The alkyl bromide reacts
from a conformation where
the leaving groups are
anti-coplanar.
Br + CH3CH2OH
+
H
C
H
C
Br
δ−
As the base removes the H+,the
double bond begins to develop
and the Br- begins to depart.
H
H
C
H
H CH3
H
C
CH3
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The E1 Reaction
The reaction of tert-butyl chloride in the mixed solvent of 80%
ethanol-20% water at 25o C yields a product mixture from two
competing reaction paths: substitution and elimination.
substitution
CH3
CH3CCl
CH3
83%
17%
elimination
CH3
CH3C-OR R = H, CH3CH2CH3
CH3
CH2=C
CH3
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A Mechanism for the Competing E1/SN1 Reactions
These two competing reactions have the same rate-determining step:
bond heterolysis to produce the tert-butyl carbocation:
bond heterolysis
CH3
RDS
CH3CCl
slow step
CH3
CH3
CH3C + +
CH3
Cl-
tert-butyl carbocation
After the rate-determining step, two competing modes of reaction
between the tert-butyl carbocation and water/ethanol (acting as
nucleophile/base) lead to substitution and elimination products.
: :
CH3
CH3C + + R-O-H
CH4 ethanol
or water
SN1
fast
E1
CH3
CH3C-OR ROH as
CH3
nucleophile
CH2=C
CH3
CH3
ROH as
base
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The E1 Path: Deprotonation Step
The substitution pathway follows the usual course for an SN1
reaction. In a fast step, the carbocation intermediate reacts with a
nucleophile (water or ethanol) to yield the substitution product.
: :
CH3
CH3C + ROH
CH3
fast
nucleophile
fast
(-H+)
CH3
CH3COR
CH3
substitution product
Along the elimination pathway, in a fast step, a base (water or
ethanol) removes a beta proton from the carbocation to produce
the alkene product.
:
R-O
H
:
H
H C
β
H
+
C
CH3
CH3
fast
ROH2
+
H
H
C
C
CH3
CH3
In the above conformation, the bonding orbital of the beta-H is
aligned with the empty p-orbital. This stereoelectronic requirement
allows immediate overlap of the developing p-orbitals of the π
bonding molecular orbital.
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Summary of Reactions
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Summary of Reactions
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ALCOHOLS
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Alcohols
Alcohols can be regarded as derivatives of water in which
one or two of the H atoms has been replaced by an alkyl
group
Water, H2O
H
O
o
0.96 A
H
104.5
Methanol, CH3OH
0.96 Ao
H C
o
O
H H
H
1.43 Ao
108.5o
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Methanol
- I (net dipole)
δ−
O δ+
H
H3C
Electronegativity of oxygen causes an
unsymmetrical distribution of charge
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Ethanol content
Beer, 3-9%
Wine, 11-13%
Whisky, 40-45%
Vanilla Extracts, 35%
Listerine, 25%
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Classification of Alcohols
H
H3C C OH
H
CH3
H3C C OH
H
CH3
H3C C OH
CH3
o
Secondary
(2
) Alcohol
Primary (1o) Alcohol
Tertiary (3o) Alcohol
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Acidity of Alcohols
Alcohols are very weak Acids
H
R O H
δ+ δ− δ+
Alcohol
H
+
R O
O H
H O H
Alkoxide
Relative Acidity ; H2O > ROH > R
2 CH3CH2OH + 2 Na
2 CH3CH2
Vigorous Reaction
C C H > RH
O
Na
+ H2
sodium ethoxide
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Preparations of Alcohols
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Hydration of Alkenes
Hydroboration-oxidation
Oxymercuration-reduction
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Prepare 1,2-diols
Hydroxyration
Acid-catalyzed hydrolysis of epoxides
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Reduction of carbonyl compounds
Sodium borohydride, NaBH4, is ususlly chosen because of its safety and
ease of handling.
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Reduction of carbonyl compounds
Lithiun aluminum hydride, LiAlH4, is more reactive reducing agent than
NaBH4. All carbonyl groups, including acids, esters, ketones, and aldehydes,
are rapidly reduced by LiAlH4. Note that one hydrogen atom is delivered to the
carbonyl carbon atom during ketone and aldehyde reductions but that two
hydrogens become bonded to the former carbonyl carbon during carboxylic
acid and ester reductions.
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Reaction of carbonyl compounds with Grignard reagents
Alkyl, aryl, and vinylic halides react with magnesium in ether or tetrahydrofuran
to generate Grignard reagents, RMgX. These Grignard reagents react with
carbonyl compounds to yield alcohols in much the same way that hydride
reducing agents do.
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Ester reaction
Carboxylic acid don’t give addition products!
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Reactions of Alcohols
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Dehydration of Alcohol to Alkenes
Dehydration is a β elimination reaction in which the elements of OH and H are
Removed from the α and β carbon atoms, respectively.
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Dehydration in Acid
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Dehydration using POCl3 and Pyridine
Because some organic compounds decompose in the presence of strong
acid. Another method to convert alcohols to alkenes has been developed by
using phosphoorus oxychloride and pyridine.
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Conversion of Alcohol to
Alkyl Halides with HX
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Mechanism
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Problem
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Solution
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Conversion of Alcohol to
Alkyl Halides with SOCl2 and PBr3
1o and 2o alcohols can be converted to alkyl halides using SOCl2 and PBr3
Phosphorus
tribromide
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Mechanism
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Mechanism
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Oxidation of Alcohols
•
Three important oxidation reagents
– Potassium permanganate (KMnO4). Deep purple in color, such a solution
is a strong oxidant. In the course of reaction, the purple Mn(VII) is reduced to
Mn(IV), which precipitates as brown manganese dioxide (MnO2).
– Chromic acid (H2CrO4). A strong oxidant usually used with alcohols,
chromic acid can be produced in solution by two methods: (1) from sodium
dichromate (Na2Cr2O7) and sulfuric acid, or (2) by dissolving chromic
anhydride (CrO3) in concentrated sulfuric acid and water (this version is
called Jones'reagent). During an oxidation reaction, the orange-colored
Cr(VI) in this reagent forms greenish-blue Cr(III), which remains in solution.
– Pyridinium chlorochromate (C5H6NCrO3Cl, PCC). A mild oxidizing
reagent, PCC is a soluble complex of chromic anhydride (CrO3) and pyridine
56
in dilute HCl.
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• Oxidation of a 1o alcohol with a strong oxidant (KMnO4 or
H2CrO4) gives a carboxylic acid.
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• An aldehyde (RCHO) can be obtained from a 1o alcohol if
PCC (pyridinium chlorochromate) is used.
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• 2o Alcohols, which have only one hydrogen bonded to
the carbon carrying the hydroxyl group, are oxidized by
chromic acid or permanganate to ketones. The oxidation
can proceed no further because the carbon doublebonded to the oxygen has no more hydrogens.
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Mechanism
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Summary Oxidation of Alcohols
•
Note that the overall change produced in the oxidation of 1o and 2o
alcohols is removal of a hydrogen from the hydroxyl group and from
the carbon to which it is attached:
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Breathalyzer Tests
When the Breathalyzer test is used for
suspected drunk drivers, the driver
exhales a volume of breath into a solution
containing the orange Cr6+ ion. If there is
ethyl alcohol present in the exhaled air,
the alcohol is oxidized, and the Cr6+ is
reduced to give a green solution of Cr3+
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ETHERS
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Acyclic Ethers
Water, H2O
H
O
0.96 Ao
Methyl ether, CH3OCH3
H
H C
O CH2CH3
Diethyl Ether
O
C H
H H H H
104.5o
CH3CH2
1.43 Ao
109.5o
H 3C O
CH3CH2
O
1.10 Ao
111.7o
Methoxy group
Ethoxy group
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Acyclic Ethers, R-O-R
Methoxycyclohexane
H3CO
O
Diethyl Ether
OCH3
1-Propoxypropane
Methoxybenzene “anisole”
Non-Flammable Anaesthetics
Cl F
F
F
H C C O C H
F
F F
Enflurane
F
H
F
C C O C H
F
F Cl
Isoflurane
Cyclic Ethers
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Reaction of Ether
Williamson Ether Synthesis
Alkoxides needed in Williamson reaction are normally prepared by reaction
of an alcohol with a strong base such as NaOH or NaH.
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Examples
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Acidic Cleavage of Ethers
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Cyclic Ethers
O
Furan
O
Tetrahydrofuran (THF)
O
Pyran
Cyclic ethers are one of the main components of epoxy glues. Such a glue is strong,
70
but also lightweight. It is used as a component of the Stealth bomber.
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Preparation of Epoxides
Mechanism
One step
Without intermediates
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